Elobixibat (1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-1′-phenyl-1′-[N′-(carboxymethyl)-carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine) is an ileal bile acid transporter (IBAT) inhibitor and can be used in the treatment of prevention of dyslipidemia (WO 02/50051), constipation (WO 2004/089350) and liver diseases such as cholestatic liver diseases and non-alcoholic steatohepatitis (WO 2012/064266).
The ileal bile acid transporter is located in the small intestine, particularly in the ileum, and is responsible for mediating the uptake of bile acids from the small intestine to the liver, as part of a process known as enterohepatic circulation. Typically, approximately 95 percent of bile acids are recirculated via the IBAT to the liver, with the remaining 5 percent being secreted to the colon. By suppressing the reabsorption of bile acids from the small intestine to the liver, an increased amount of bile acids is secreted to the colon. The higher concentration of bile acids in the colon in turn leads to an increased secretion of electrolytes and water, resulting in a softening of the stool and higher motility in the large bowel. As an inhibitor of the ileal bile acid transporter, elobixibat may therefore be used in the treatment of constipation.
The preparation of elobixibat and several related 1,5-benzothiazepine compounds is disclosed in WO 02/50051. The preparation of elobixibat comprised a large number of consecutive steps, and involved several reagents that are less desirable from an environmental or safety perspective. The purification of the final product (elobixibat) and several of the intermediate products required preparative chromatography, which works well for small scale synthesis but which is less suitable for industrial scale production.
Several stable crystal modifications of elobixibat have been disclosed in WO 2014/174066 and WO 2016/062848, including crystal modification IV of elobixibat. However, the methods for obtaining the hydrate and anhydrate forms described in these documents are not optimized for production on an industrial scale.
Thus, there is a need for an improved process for the preparation of elobixibat, or a crystalline monohydrate thereof such as crystal modification IV. Such process should make it possible to produce elobixibat on an industrial scale, and in higher yields and higher purity than previously described processes.